Epigenetic regulation in cancer progression

Cell & Bioscience

Jason S Lee¹  Frank Gannon¹  Karolina Windloch¹  Eva Baxter¹ 

[1] QIMR Berghofer Medical Research Institute, Control of Gene Expression Laboratory, Herston Rd, 4006 Herston, QLD, Australia

关键词: Transcription;    Demethylation;    Acetylation;    Histone modifications;    DNA methylation;    Cancer;    Hypoxia;    Epigenetics;   

Others  :  1149437
DOI  :  10.1186/2045-3701-4-45

 received in 2014-05-26, accepted in 2014-07-26,  发布年份 2014

【 摘 要 】

Cancer is a disease arising from both genetic and epigenetic modifications of DNA that contribute to changes in gene expression in the cell. Genetic modifications include loss or amplification of DNA, loss of heterozygosity (LOH) as well as gene mutations. Epigenetic changes in cancer are generally thought to be brought about by alterations in DNA and histone modifications that lead to the silencing of tumour suppressor genes and the activation of oncogenic genes. Other consequences that result from epigenetic changes, such as inappropriate expression or repression of some genes in the wrong cellular context, can also result in the alteration of control and physiological systems such that a normal cell becomes tumorigenic. Excessive levels of the enzymes that act as epigenetic modifiers have been reported as markers of aggressive breast cancer and are associated with metastatic progression. It is likely that this is a common contributor to the recurrence and spread of the disease. The emphasis on genetic changes, for example in genome-wide association studies and increasingly in whole genome sequencing analyses of tumours, has resulted in the importance of epigenetic changes having less attention until recently. Epigenetic alterations at both the DNA and histone level are increasingly being recognised as playing a role in tumourigenesis. Recent studies have found that distinct subgroups of poor-prognosis tumours lack genetic alterations but are epigenetically deregulated, pointing to the important role that epigenetic modifications and/or their modifiers may play in cancer. In this review, we highlight the multitude of epigenetic changes that can occur and will discuss how deregulation of epigenetic modifiers contributes to cancer progression. We also discuss the off-target effects that epigenetic modifiers may have, notably the effects that histone modifiers have on non-histone proteins that can modulate protein expression and activity, as well as the role of hypoxia in epigenetic regulation.

【 授权许可】

   
2014 Baxter et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Jones PA, Laird PW: Cancer-epigenetics comes of age. Nat Genet 1999, 21(2):163-167.
• [2]Stein R, Razin A, Cedar H: In vitro methylation of the hamster adenine phosphoribosyltransferase gene inhibits its expression in mouse L cells. Proc Natl Acad Sci 1982, 79(11):3418-3422.
• [3]Dodge JE, Ramsahoye BH, Wo ZG, Okano M, Li E: De novo methylation of MMLV provirus in embryonic stem cells: CpG versus non-CpG methylation. Gene 2002, 289(1–2):41-48.
• [4]Okano M, Bell W, Haber DA, Li E: DNA Methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 1999, 99(3):247-257.
• [5]Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y, Agarwal S, Iyer LM, Liu DR, Aravind L, Rao A: Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 2009, 324(5929):930-935.
• [6]Lister R, Pelizzola M, Dowen RH, Hawkins RD, Hon G, Tonti-Filippini J, Nery JR, Lee L, Ye Z, Ngo Q-M, Edsall L, Antosiewicz-Bourget J, Stewart R, Ruotti V, Millar AH, Thomson JA, Ren B, Ecker JR: Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 2009, 462(7271):315-322.
• [7]Ramsahoye BH, Biniszkiewicz D, Lyko F, Clark V, Bird AP, Jaenisch R: Non-CpG methylation is prevalent in embryonic stem cells and may be mediated by DNA methyltransferase 3a. Proc Natl Acad Sci 2000, 97(10):5237-5242.
• [8]Ito S, Shen L, Dai Q, Wu SC, Collins LB, Swenberg JA, He C, Zhang Y: Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science 2011, 333(6047):1300-1303.
• [9]Strahl BD, Allis CD: The language of covalent histone modifications. Nature 2000, 403(6765):41-45.
• [10]Chi P, Allis CD, Wang GG: Covalent histone modifications — miswritten, misinterpreted and mis-erased in human cancers. Nat Rev Cancer 2010, 10(7):457-469.
• [11]Barth TK, Imhof A: Fast signals and slow marks: the dynamics of histone modifications. Trends Biochem Sci 2010, 35(11):618-626.
• [12]Bernstein BE, Mikkelsen TS, Xie X, Kamal M, Huebert DJ, Cuff J, Fry B, Meissner A, Wernig M, Plath K, Jaenisch R, Wagschal A, Feil R, Schreiber SL, Lander ES: A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 2006, 125(2):315-326.
• [13]Ley TJ, Ding L, Walter MJ, McLellan MD, Lamprecht T, Larson DE, Kandoth C, Payton JE, Baty J, Welch J, Harris CC, Lichti CF, Townsend RR, Fulton RS, Dooling DJ, Koboldt DC, Schmidt H, Zhang Q, Osborne JR, Lin L, O’Laughlin M, McMichael JF, Delehaunty KD, McGrath SD, Fulton LA, Magrini VJ, Vickery TL, Hundal J, Cook LL, Conyers JJ, et al.: DNMT3A mutations in acute myeloid leukemia. New Engl J Med 2010, 363(25):2424-2433.
• [14]Delhommeau F, Dupont S, Valle VD, James C, Trannoy S, Massé A, Kosmider O, Le Couedic J-P, Robert F, Alberdi A, Lécluse Y, Plo I, Dreyfus FJ, Marzac C, Casadevall N, Lacombe C, Romana SP, Dessen P, Soulier J, Viguié F, Fontenay M, Vainchenker W, Ber OA: Mutation in TET2 in myeloid cancers. N Engl J Med 2009, 360(22):2289-2301.
• [15]Moran-Crusio K, Reavie L, Shih A, Abdel-Wahab O, Ndiaye-Lobry D, Lobry C, Figueroa ME, Vasanthakumar A, Patel J, Zhao X, Perna F, Pandey S, Madzo J, Song C, Dai Q, He C, Ibrahim S, Beran M, Zavadil J, Nimer SD, Melnick A, Godley LA, Aifantis I, Levine RL: Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer Cell 2011, 20(1):11-24.
• [16]van Haaften G, Dalgliesh GL, Davies H, Chen L, Bignell G, Greenman C, Edkins S, Hardy C, O’Meara S, Teague J, Butler A, Hinton J, Latimer C, Andrews J, Barthorpe S, Beare D, Buck G, Campbell PJ, Cole J, Forbes S, Jia M, Jones D, Kok CY, Leroy C, Lin M-L, McBride DJ, Maddison M, Maquire S, McLay K, Menz A: Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer. Nat Genet 2009, 41(5):521-523.
• [17]Gelsi-Boyer V, Trouplin V, Adélaïde J, Bonansea J, Cervera N, Carbuccia N, Lagarde A, Prebet T, Nezri M, Sainty D, Olschwang S, Xerri L, Chaffanet M, Mozziconacci M-J, Vey N, Birnbaum D: Mutations of polycomb-associated gene ASXL1 in myelodysplastic syndromes and chronic myelomonocytic leukaemia. Br J Haematol 2009, 145(6):788-800.
• [18]Bird A: DNA methylation patterns and epigenetic memory. Genes Dev 2002, 16(1):6-21.
• [19]Greger V, Debus N, Lohmann D, Hopping W, Passarge E, Horsthemke B, Debus N, Lohmann D, Hopping W, Passarge E, Horsthemke B: Frequency and parental origin of hypermethylated RB1 alleles in retinoblastoma. Hum Genet 1994, 94(5):491-496.
• [20]Ohtani-Fujita N, Fujita T, Aoike A, Osifchin N, Robbins P, Sakai T: CpG methylation inactivates the promoter activity of the human retinoblastoma tumor-suppressor gene. Oncogene 1993, 8(4):1063-1067.
• [21]Stirzaker C, Millar DS, Paul CL, Warnecke PM, Harrison J, Vincent PC, Frommer M, Clark SJ, Millar DS, Paul CL, Warnecke PM, Harrison J, Vincent PC, Frommer M, Clark SJ: Extensive DNA methylation spanning the Rb promoter in retinoblastoma tumors. Cancer Res 1997, 57(11):2229-2237.
• [22]Papadopoulos N, Nicolaides N, Wei Y, Ruben S, Carter K, Rosen C, Haseltine W, Fleischmann R, Fraser C, Adams M, Venter C, Hamilton SR, Petersen GM, Watson P, Lynch HT, Peltomäki P, Jukka-Pekka Mecklin J, de la Chapell A: Mutation of a mutL homolog in hereditary colon cancer. Science 1994, 263(5153):1625-1629.
• [23]Furukawa T, Konishi F, Masubuchi S, Shitoh K, Nagai H, Tsukamoto T: Densely methylated MLH1 promoter correlates with decreased mRNA expression in sporadic colorectal cancers. Genes Chr Cancer 2002, 35(1):1-10.
• [24]Kane MF, Loda M, Gaida GM, Lipman J, Mishra R, Goldman H, Jessup JM, Kolodner R: Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. Cancer Res 1997, 57(5):808-811.
• [25]Herman JG, Umar A, Polyak K, Graff JR, Ahuja N, Issa J-PJ, Markowitz S, Willson JKV, Hamilton SR, Kinzler KW, Kane MF, Kolodner RD, Vogelstein B, Kunkel TA, Baylin SB: Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci 1998, 95(12):6870-6875.
• [26]Belinsky SA, Nikula KJ, Palmisano WA, Michels R, Saccomanno G, Gabrielson E, Baylin SB, Herman JG: Aberrant methylation of p16INK4a is an early event in lung cancer and a potential biomarker for early diagnosis. Proc Natl Acad Sci 1998, 95(20):11891-11896.
• [27]Lee WH, Morton RA, Epstein JI, Brooks JD, Campbell PA, Bova GS, Hsieh WS, Isaacs WB, Nelson WG: Cytidine methylation of regulatory sequences near the pi-class glutathione S-transferase gene accompanies human prostatic carcinogenesis. Proc Natl Acad Sci 1994, 91(24):11733-11737.
• [28]Makos M, Nelkin BD, Lerman MI, Latif F, Zbar B, Baylin SB: Distinct hypermethylation patterns occur at altered chromosome loci in human lung and colon cancer. Proc Natl Acad Sci 1992, 89(5):1929-1933.
• [29]Vogelstein B, Nelkin BD, Lerman MI, Latif F, Zbar B, Baylin SB: Genetic alterations during colorectal-tumor development. New Engl J Med 1988, 319(9):525-532.
• [30]Clark SJ, Melki J: DNA methylation and gene silencing in cancer: which is the guilty party? Oncogene 2002, 21:5380-5387.
• [31]Christensen BC, Marsit CJ, Houseman EA, Godleski JJ, Longacker JL, Zheng S, Yeh R-F, Wrensch MR, Wiemels JL, Karagas MR, Bueno R, Sugarbaker DJ, Nelson HH, Wiencke JK, Kelsey KT: Differentiation of lung adenocarcinoma, pleural mesothelioma, and nonmalignant pulmonary tissues using DNA methylation profiles. Cancer Res 2009, 69(15):6315-6321.
• [32]Toyota M, Ahuja N, Ohe-Toyota M, Herman JG, Baylin SB, Issa J-PJ: CpG island methylator phenotype in colorectal cancer. Proc Natl Acad Sci 1999, 96(15):8681-8686.
• [33]Weisenberger DJ, Siegmund KD, Campan M, Young J, Long TI, Faasse MA, Kang GH, Widschwendter M, Weener D, Buchanan D, Koh H, Simms L, Barker M, Leggett B, Levine J, Kim M, French AJ, Thibodeau SN, Jass J, Haile R, Laird PW: CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet 2006, 38(7):787-793.
• [34]Noushmehr H, Weisenberger DJ, Diefes K, Phillips HS, Pujara K, Berman BP, Pan F, Pelloski CE, Sulman EP, Bhat KP, Verhaak RGW, Hoadley KA, Hayes DN, Perou CM, Schmidt HK, Ding L, Wilson RK, Van Den Berg D, Shen H, Bengtsson H, Neuvial P, Cope LM, Buckley J, Herman JG, Baylin SB, Laird PW, Aldape K: Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 2010, 17(5):510-522.
• [35]Figueroa ME, Abdel-Wahab O, Lu C, Ward PS, Patel J, Shih A, Li Y, Bhagwat N, Vasanthakumar A, Fernandez HF, Tallman MS, Sun Z, Wolniak K, Peeters JK, Liu W, Choe SE, Fantin VR, Paietta E, Löwenberg B, Licht JD, Godley LA, Delwel R, Valk PJM, Thompson CB, Levine RL, Melnick A: Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 2010, 18(6):553-567.
• [36]Zouridis H, Abdel-Wahab O, Lu C, Ward PS, Patel J, Shih A, Li Y, Bhagwat N, Vasanthakumar A, Fernandez HF, Tallman MS, Sun Z, Wolniak K, Peeters JK, Liu W, Choe SE, Fantin VR, Paietta E, Löwenberg B, Licht JD, Godley LA, Delwel R, Valk PJM, Thompson CB, Levine RL, Melnick A: Methylation subtypes and large-scale epigenetic alterations in gastric cancer. Sci Transl Med 2012, 4(156):156ra140.
• [37]Mack SC, Witt H, Piro RM, Gu L, Zuyderduyn S, Stutz AM, Wang X, Gallo M, Garzia L, Zayne K, Zhang X, Ramaswamy V, Jager N, Jones DTW, Sill M, Pugh TJ, Ryzhova M, Wani KM, Shih DJH, Head R, Remke M, Bailey SD, Zichner T, Faria CC, Barszczyk M, Stark S, Seker-Cin H, Hutter S, Johann P, Bender S: Epigenomic alterations define lethal CIMP-positive ependymomas of infancy. Nature 2014, 506(7489):445-450.
• [38]Feinberg AP, Gehrke CW, Kuo KC, Ehrlich M: Reduced genomic 5-methylcytosine content in human colonic neoplasia. Cancer Res 1988, 48(5):1159-1161.
• [39]Gama-Sosa M, Slagel V, Trewyn R, Oxenhandler R, Kuo K, Gehrke C, Ehrlich M: The 5-methylcytosine content of DNA from human tumors. Nucl Acids Res 1983, 11(19):6883-6894.
• [40]Goelz S, Vogelstein B, Hamilton S, Feinberg A: Hypomethylation of DNA from benign and malignant human colon neoplasms. Science 1985, 228(4696):187-190.
• [41]Mertineit C, Yoder JA, Taketo T, Laird DW, Trasler JM, Bestor TH: Sex-specific exons control DNA methyltransferase in mammalian germ cells. Development 1998, 125(5):889-897.
• [42]Wossidlo M, Nakamura T, Lepikhov K, Marques CJ, Zakhartchenko V, Boiani M, Arand J, Nakano T, Reik W, Walter J: 5-Hydroxymethylcytosine in the mammalian zygote is linked with epigenetic reprogramming. Nat Commun 2011, 2:241.
• [43]Valinluck V, Sowers LC: Endogenous cytosine damage products alter the site selectivity of human DNA maintenance methyltransferase DNMT1. Cancer Res 2007, 67(3):946-950.
• [44]Guo JU, Su Y, Zhong C, Ming G-l, Song H: Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain. Cell 2011, 145(3):423-434.
• [45]He Y-F, Li B-Z, Li Z, Liu P, Wang Y, Tang Q, Ding J, Jia Y, Chen Z, Li L, Sun Y, Li X, Dai Q, Song C-X, Zhang K, He C, Xu G-L: Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science 2011, 333(6047):1303-1307.
• [46]Maiti A, Drohat AC: Thymine DNA glycosylase can rapidly excise 5-formylcytosine and 5-carboxylcytosine: potential implications for active demethylation of CpG sites. J Biol Chem 2011, 286(41):35334-35338.
• [47]Kangaspeska S, Stride B, Métivier R, Polycarpou-Schwarz M, Ibberson D, Carmouche RP, Benes V, Gannon F, Reid G: Transient cyclical methylation of promoter DNA. Nature 2008, 452(7183):112-115.
• [48]Metivier R, Gallais R, Tiffoche C, Le Peron C, Jurkowska RZ, Carmouche RP, Ibberson D, Barath P, Demay F, Reid G, Benes V, Jeltsch A, Gannon F, Salbert G: Cyclical DNA methylation of a transcriptionally active promoter. Nature 2008, 452(7183):45-50.
• [49]Ko M, Huang Y, Jankowska AM, Pape UJ, Tahiliani M, Bandukwala HS, An J, Lamperti ED, Koh KP, Ganetzky R, Liu XS, Aravind L, Agarwal S, Maciejewski JP, Rao A: Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. Nature 2010, 468(7325):839-843.
• [50]Yang H, Liu Y, Bai F, Zhang JY, Ma SH, Liu J, Xu ZD, Zhu HG, Ling ZQ, Ye D, Guan KL, Xiong Y: Tumor development is associated with decrease of TET gene expression and 5-methylcytosine hydroxylation. Oncogene 2013, 32(5):663-669.
• [51]Jenuwein T, Allis CD: Translating the histone code. Science 2001, 293(5532):1074-1080.
• [52]Rice JC, Briggs SD, Ueberheide B, Barber CM, Shabanowitz J, Hunt DF, Shinkai Y, Allis CD: Histone methyltransferases direct different degrees of methylation to define distinct chromatin domains. Mol Cell 2003, 12(6):1591-1598.
• [53]Feinberg AP, Tycko B: The history of cancer epigenetics. Nat Rev Cancer 2004, 4(2):143-153.
• [54]Dong C, Wu Y, Yao J, Wang Y, Yu Y, Rychahou PG, Evers BM, Zhou BP: G9a interacts with snail and is critical for snail-mediated E-cadherin repression in human breast cancer. J Clin Invest 2012, 122(4):1469-1486.
• [55]Chen M-W, Hua K-T, Kao H-J, Chi C-C, Wei L-H, Johansson G, Shiah S-G, Chen PS, Jeng Y-M, Cheng T-Y, Lai T-C, Chang J-S, Jan Y-H, Chien M-H, Yang C-J, Huang M-S, Hsiao M, Kuo M-L: H3K9 histone methyltransferase G9a promotes lung cancer invasion and metastasis by silencing the cell adhesion molecule Ep-CAM. Cancer Res 2010, 70(20):7830-7840.
• [56]Kleer CG, Cao Q, Varambally S, Shen R, Ota I, Tomlins SA, Ghosh D, Sewalt RGAB, Otte AP, Hayes DF, Sabel MS, Livant D, Weiss SJ, Rubin MA, Chinnaiyan AM: EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc Natl Acad Sci 2003, 100(20):11606-11611.
• [57]Varambally S, Dhanasekaran SM, Zhou M, Barrette TR, Kumar-Sinha C, Sanda MG, Ghosh D, Pienta KJ, Sewalt RGAB, Otte AP, Rubin MA, Chinnaiyan AM: The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 2002, 419(6907):624-629.
• [58]Agger K, Cloos PAC, Rudkjær L, Williams K, Andersen G, Christensen J, Helin K: The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A–ARF locus in response to oncogene- and stress-induced senescence. Genes Dev 2009, 23(10):1171-1176.
• [59]Song JS, Kim YS, Kim DK, Park SI, Jang SJ: Global histone modification pattern associated with recurrence and disease-free survival in non-small cell lung cancer patients. Pathol Intl 2012, 62(3):182-190.
• [60]Seligson DB, Horvath S, Shi T, Yu H, Tze S, Grunstein M, Kurdistani SK: Global histone modification patterns predict risk of prostate cancer recurrence. Nature 2005, 435(7046):1262-1266.
• [61]Müller-Tidow C, Klein H-U, Hascher A, Isken F, Tickenbrock L, Thoennissen N, Agrawal-Singh S, Tschanter P, Disselhoff C, Wang Y, Becker A, Thiede C, Ehninger G, Zur Stadt U, Koschmieder S, Seidl M, Müller FU, Schmitz W, Schlenke P, McClelland M, Berdel WE, Dugas M, Serve H, Study A L: Profiling of histone H3 lysine 9 trimethylation levels predicts transcription factor activity and survival in acute myeloid leukemia. Blood 2010, 116(18):3564-3571.
• [62]Chen H, Yan Y, Davidson TL, Shinkai Y, Costa M: Stress induces dimethylated histone cells. Cancer Res 2006, 66(18):9009-9016.
• [63]Lee JS, Kim Y, Kim IS, Kim B, Choi HJ, Lee JM, Shin H-JR, Kim JH, Kim J-Y, Seo S-B, Lee H, Binda O, Gozani O, Semenza GL, Kim M, Kim KI, Hwang D, Baek SH: Negative regulation of hypoxic responses via induced reptin methylation. Mol Cell 2010, 39(1):71-85.
• [64]Lee JS, Kim Y, Bhin J, Shin H-JR, Nam HJ, Lee SH, Yoon J-B, Binda O, Gozani O, Hwang D, Baek SH, Kim Y, Bhin J, Shin H-JR, Nam HJ, Lee SH, Yoon J-B, Binda O, Gozani O, Hwang D, Baek SH: Hypoxia-induced methylation of a pontin chromatin remodeling factor. Proc Natl Acad Sci 2011, 108(33):13510-13515.
• [65]Shi Y, Lan F, Matson C, Mulligan P, Whetstine JR, Cole PA, Casero RA, Shi Y, Lan F, Matson C, Mulligan P, Whetstine JR, Cole PA, Casero RA, Shi Y, Lan F, Matson C, Mulligan P, Whetstine JR, Cole PA, Casero RA, Shi Y: Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 2004, 119(7):941-953.
• [66]Huang Y, Lan F, Matson C, Mulligan P, Whetstine JR, Cole PA, Casero RA, Shi Y: Inhibition of lysine-specific demethylase 1 by polyamine analogues results in reexpression of aberrantly silenced genes. Proc Natl Acad Sci 2007, 104(19):8023-8028.
• [67]Ng SS, Kavanagh KL, McDonough MA, Butler D, Pilka ES, Lienard BMR, Bray JE, Savitsky P, Gileadi O, von Delft F, Rose NR, Offer J, Scheinost JC, Borowski T, Sundstrom M, Schofield CJ, Oppermann U: Crystal structures of histone demethylase JMJD2A reveal basis for substrate specificity. Nature 2007, 448(7149):87-91.
• [68]Okada Y, Scott G, Ray MK, Mishina Y, Zhang Y: Histone demethylase JHDM2A is critical for Tnp1 and Prm1 transcription and spermatogenesis. Nature 2007, 450(7166):119-123.
• [69]Wang J, Hevi S, Kurash JK, Lei H, Gay F, Bajko J, Su H, Sun W, Chang H, Xu G, Gaudet F, Li E, Chen T: The lysine demethylase LSD1 (KDM1) is required for maintenance of global DNA methylation. Nat Genet 2009, 41(1):125-129.
• [70]Takeuchi T, Yamazaki Y, Katoh-Fukui Y, Tsuchiya R, Kondo S, Motoyama J, Higashinakagawa T: Gene trap capture of a novel mouse gene, jumonji, required for neural tube formation. Genes Dev 1995, 9(10):1211-1222.
• [71]Chuikov S, Kurash JK, Wilson JR, Xiao B, Justin N, Ivanov GS, McKinney K, Tempst P, Prives C, Gamblin SJ, Barlev NA, Reinberg D: Regulation of p53 activity through lysine methylation. Nature 2004, 432(7015):353-360.
• [72]Huang J, Perez-Burgos L, Placek BJ, Sengupta R, Richter M, Dorsey JA, Kubicek S, Opravil S, Jenuwein T, Berger SL: Repression of p53 activity by Smyd2-mediated methylation. Nature 2006, 444(7119):629-632.
• [73]Huang J, Sengupta R, Espejo AB, Lee MG, Dorsey JA, Richter M, Opravil S, Shiekhattar R, Bedford MT, Jenuwein T, Berger SL: p53 is regulated by the lysine demethylase LSD1. Nature 2007, 449(7158):105-108.
• [74]Huang J, Dorsey J, Chuikov S, Zhang X, Jenuwein T, Reinberg D, Berger SL: G9a and Glp methylate Lysine 373 in the tumor suppressor p53. J Biol Chem 2010, 285(13):9636-9641.
• [75]Kim E, Kim M, Woo D-H, Shin Y, Shin J, Chang N, Oh YT, Kim H, Rheey J, Nakano I, Lee C, Joo KM, Rich JN, Nam D-H, Lee J: Phosphorylation of EZH2 activates STAT3 signaling via STAT3 methylation and promotes tumorigenicity of glioblastoma stem-like cells. Cancer Cell 2013, 23(6):839-852.
• [76]He A, Shen X, Ma Q, Cao J, von Gise A, Zhou P, Wang G, Marquez VE, Orkin SH, Pu WT: PRC2 directly methylates GATA4 and represses its transcriptional activity. Genes Dev 2012, 26(1):37-42.
• [77]Lee JM, Lee JS, Kim H, Kim K, Park H, Kim J-Y, Seung H, Lee SH, Kim LKS, Kim J, Lee M, Chung CH, Seo S-B, Yoon J-B, Ko E, Noh D-Y, Keun I, Kim KI, Kim KK, Baek SH: EZH2 generates a methyl degron that is recognized by the DCAF1/DDB1/CUL4 E3 ubiquitin ligase complex. Mol Cell 2012, 48(4):572-586.
• [78]Bertout JA, Patel SA, Simon MC: The impact of O2 availability on human cancer. Nat Rev Cancer 2008, 8(12):967-975.
• [79]Borger DR, Gavrilescu LC, Bucur MC, Ivan M, Decaprio JA: AMP-activated protein kinase is essential for survival in chronic hypoxia. Biochem Biophys Res Commun 2008, 370(2):230-234.
• [80]Fukuda R, Zhang H, Kim JW, Shimoda L, Dang CV, Semenza GL, Zhang H, Kim JW, Shimoda L, Dang CV, Semenza GL: HIF-1 regulates cytochrome oxidase subunits to optimize efficiency of respiration in hypoxic cells. Cell 2007, 129(1):111-122.
• [81]Semenza GL: HIF-1: upstream and downstream of cancer metabolism. Curr Opin Genet Dev 2010, 20(1):51-56.
• [82]Harris AL: Hypoxia–a key regulatory factor in tumour growth. Nat Rev Cancer 2002, 2(1):38-47.
• [83]Majmundar AJ, Wong WJ, Simon MC: Hypoxia-inducible factors and the response to hypoxic stress. Mol Cell 2010, 40(2):294-309.
• [84]Ema M, Taya S, Yokotani N, Sogawa K, Matsuda Y, Fujii-Kuriyama Y: A novel bHLH-PAS factor with close sequence similarity to hypoxia-inducible factor 1α regulates the VEGF expression and is potentially involved in lung and vascular development. Proc Natl Acad Sci 1997, 94(9):4273-4278.
• [85]Semenza GL, Wang GL: A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol 1992, 12(12):5447-5454.
• [86]Ivanov SV, Salnikow K, Ivanova AV, Bai L, Lerman MI: Hypoxic repression of STAT1 and its downstream genes by a pVHL/HIF-1 target DEC1/STRA13. Oncogene 2007, 26(6):802-812.
• [87]Lee SH, Kim J, Kim WH, Lee YM: Hypoxic silencing of tumor suppressor RUNX3 by histone modification in gastric cancer cells. Oncogene 2008, 28(2):184-194.
• [88]Pathiraja TN, Nayak SR, Xi Y, Jiang S, Garee JP, Edwards DP, Lee AV, Chen J, Shea MJ, Santen RJ, Gannon F, Kangaspeska S, Jelinek J, Issa J-PJ, Richer JK, Elias A, McIlroy M, Young LS, Davidson NE, Schiff R, Li W, Oesterreich S: Epigenetic reprogramming of HOXC10 in endocrine-resistant breast cancer. Sci Transl Med 2014, 6(229):229ra41.